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Endocrinology and diabetes
Published in Shibley Rahman, Avinash Sharma, A Complete MRCP(UK) Parts 1 and 2 Written Examination Revision Guide, 2018
Shibley Rahman, Avinash Sharma
Liddle’s syndrome is a rare autosomal dominant condition that causes hypertension and hypokalaemic alkalosis. It is thought to be caused by a disorder of sodium channels in the distal tubules leading to increased re-absorption of sodium.
Nephrology
Published in John D Firth, Professor Ian Gilmore, MRCP Part 1 Self-Assessment, 2017
John D Firth, Professor Ian Gilmore
Liddle’s syndrome is caused by a mutation in the sodium channel (ENaC) in the distal nephron. The mutation keeps the channel open, which has a similar effect to a raised aldosterone level, including increased potassium excretion leading to hypokalaemia. Aldosterone levels are not raised and may be lowered as a result of feedback from sodium and water retention. The condition is sometimes called pseudohyperaldosteronism.
Endocrine hypertension
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Frances McManus, John M. Connell, Marie Freel
Liddle’s syndrome is a rare, autosomal dominant condition and associated with moderate-to-severe hypertension presenting in childhood, arising from over activation of the epithelial sodium channel (ENaC). In common with PA, patients are hypokalemic with a metabolic alkalosis and have a low plasma renin, but in this case plasma aldosterone concentrations are low.30 The genetic abnormality lies on chromosome 16, and “gain-of-function mutations” identified to date lie in the cytoplasmic C-terminal tails of the β- and γ-subunits of ENaC.31 These mutations result in loss of an adaptor motif that interacts with neural precursor cell-expressed, developmentally down regulated 4-2 (Nedd4-2). Nedd4-2 ligates a ubiquitin “tag” to the ENaC that targets it for internalization and subsequent destruction. This induces constitutive activity of the ENaC in the cortical collecting duct, as if activated by aldosterone. Importantly, in this condition, spironolactone is not effective because activation of ENaC is not due to excessive aldosterone levels and is independent of the MR. However, the ENaC is amiloride sensitive, and this is the treatment of choice in these patients.
Liddle syndrome misdiagnosed as primary aldosteronism is caused by inaccurate aldosterone-rennin detection while a novel SCNN1G mutation is discovered
Published in Blood Pressure, 2022
Yaling Yang, Chenwei Wu, Duoduo Qu, Xinyue Xu, Lili Chen, Quanya Sun, Xiaolong Zhao
Hypertension combined with hypokalaemia is common in clinical practice. However, only a tiny part of it could be explained by Liddle syndrome. Liddle syndrome mimics the symptoms of mineralocorticoid excess characterised by early-onset hypertension, hypokalaemia, and metabolic alkalosis. Liddle syndrome is an autosomal dominant disease, first reported by Liddle in 1963 [1] Mutations in the subunits of ENaC lead to over activation of the channel, which presents clinically as volume expansion and inhibition of aldosterone-renin levels. Treatments of salt restriction and the using ENaC inhibitors (amiloride, triamterene) are usually effective. There is no specific diagnosing process in any guideline for Liddle syndrome at present and endocrinologists usually apply the flow chart of hypertension and hypokalaemia to discriminate a cluster of endocrine hypertension [2]. Accurate detection of aldosterone levels and aldosterone-rennin ratio (ARR) is important because it is the key point of the flow chart. Meanwhile, a genetic test is recommended for early-onset hypertension and familial hypertension to confirm hereditary hypertension [3].
A novel nonsense mutation in the β-subunit of the epithelial sodium channel causing Liddle syndrome
Published in Blood Pressure, 2021
Štěpán Mareš, Jan Filipovský, Kateřina Vlková, Martin Pešta, Václava Černá, Jaroslav Hrabák, Jitka Mlíková Seidlerová, Otto Mayer
Liddle syndrome (LS) is a hereditary form of arterial hypertension. Its key clinical characteristics are early onset of hypertension, hypokalaemia and suppressed plasma renin and aldosterone levels. It is a monogenic form of hypertension with an autosomal dominant pattern of inheritance [1]. LS is caused by activating mutations of epithelial sodium channel (ENaC) which is mainly expressed in aldosterone-sensitive distal nephron (Figure 1). ENaC is responsible for reabsorption of sodium, maintaining body salt and water homeostasis. This channel is composed of three homologous subunits (α-, β-, γ-) encoded by the genes SCNN1A, SCNN1B and SCNN1G [2,3]. Each subunit consists of cytoplasmic amino acid and carboxyl termini, two transmembrane domains, and a large extracellular loop. Carboxyl terminus contains sites of interaction with other proteins and signal transduction molecules that regulate ENaC function. Within the C-terminus of all three subunits there is a highly conserved sequence of amino acids named “PY motif” – a proline rich sequence which is a binding site for ubiquitin-protein ligase NEDD4 [3,4]. NEDD4 mediates the internalisation and degradation of ENaC. In general, mutations causing Liddle syndrome result in increased activity of ENaC. Most of them cause disruption or loss of PY motif of β or γ subunits and therefore impaired channel degradation (Figure 2). Additional mechanism such as disruption of disulphide bridge in extracellular loop of α subunit leading to elevation of channel open probability has been described as well [5–7].
Epithelial sodium channel blockade and new β-ENaC polymorphisms among normotensive and hypertensive adult Nigerians
Published in Clinical and Experimental Hypertension, 2019
Simiat O. Elias, Olusoga A. Sofola, Smith I. Jaja
The relationship between SCNN1B and systolic blood pressure has been investigated in different populations such as Black Americans (16), South Africans (17), the Japanese (18), and Indians of Indo-Aryan ancestry (19) with variable results. A missense mutation in the β-subunit of ENaC (T594M allele of SCNN1B or β-ENaC) has been implicated as a gain-of-function mutation as in Liddle syndrome causing impaired renal sodium excretion and salt-sensitive hypertension (1). The β-T594M polymorphism has also been associated with increased blood pressure in an English population of African ancestry and Ghanaians in Kumasi (20) whereas no similar association was found in a South African population although the β-R563Q mutation of ENaC has been associated with preeclampsia in South African blacks of mixed ancestry (21,22). Similarly, there was no association between β-T594M polymorphism and the prevalence of hypertension or untreated blood pressure in two independent groups of black individuals from the Dallas Heart Study in Texas and the Spanish Town study in Jamaica (23) while Gupta et al. (19) reported a non-polymorphic T594M mutation with no relationship to the development or course of hypertension among the Indo-Aryans. Based on this racial component in the activity, we set out to investigate the presence of β-ENaC polymorphisms as well as the effect of the blockade of the channel with amiloride among Nigerian blacks living in Lagos.